- Visiting Professor (Institute of Infection Immunity and Inflammation)
My group has identified cellular proteins and pathways that functionally interact with human papillomavirus replication, transcription and genome segregation functions. The ultimate purpose of our work is to increase our understanding of the viral life cycle and identify novel anti-viral targets with therapeutic potential. The viral protein HPV 16 E2 is an essential factor for regulating viral transcription, replication (in association with E1) and genome segregation. In replication, E2 binds to target DNA sequences surrounding the viral origin and recruits E1 via a protein-protein interaction. The E1 protein then recognises the viral origin and forms a di-hexameric helicase complex responsible for genome replication. In genome segregation, E2 associates with mitotic chromatin and the viral genome simultaneously allowing distribution of the viral genome into daughter cells following cell division. My lab has identified the cellular replication factor TopBP1 as a binding partner for E2 and using mutation screening demonstrated that this interaction is required for efficient E2-E1 mediated DNA replication and also for the association of E2 with mitotic chromatin. We have also demonstrated that TopBP1 interacts with E1 and evidence suggests a triple complex between E2-E1-TopBP1 that is required for optimum viral genome replication and we are currently testing this hypothesis. There are two crucial novel aspects to these observations; firstly that E2 regulates viral replication not simply by recruiting E1 but also by interacting with cellular proteins; and secondly that TopBP1 is the mitotic chromatin receptor for HPV16 E2.
Current collaborations on this project are with Dr Joanne Parish, University of St Andrews, where we are working towards a crystal structure for the E2-TopBP1 interaction; and with Professor Peter Howley, Harvard Medical School, where we are using advanced proteomic techniques to identify differences in replication complexes when E2 fails to bind to TopBP1.
The overall goal of these studies is to develop the E2-E1-TopBP1 complex as an anti-viral target and also to improve our understanding of the role of TopBP1 in replication in mammalian cells.